Maclpil is a proinflammatory long non-coding RNA highly expressed on monocyte-derived macrophages in the ischemic brain. This study investigated the impact and the mechanisms of systemically delivering nanoparticle Maclpil short interfering RNA (siRNA) on experimental ischemic stroke in a mouse model.
Ischemic stroke (focal cerebral ischemia) was induced in male C57BL/6 mice through the middle cerebral artery occlusion. Three hours thereafter, mice were intravenously injected with Maclpil siRNA or scramble siRNA nanoparticles. Bone marrow cell-derived macrophages were transfected with Maclpil or scramble siRNA and subjected to oxygen glucose deprivation culture. The influence of silencing Maclpil on stroke outcomes, neuroinflammation, and macrophage fates was assessed
Three days following stroke induction, siRNA silencing Maclpil substantially reduced ischemic infarction size and improved neurological behaviors. Silencing Maclpil also markedly attenuated the accumulation of monocyte-derived macrophages, CD4+ T cells, and CD8+ T cells in the ischemic hemisphere without affecting microglia cellularity. Reciprocally, myeloid cells and both subsets of T cells were elevated in mouse peripheral blood following Maclpil siRNA treatment. Under oxygen glucose deprivation conditions that mimicked hypoxia and hypoglycemia
Systemically silencing Maclpil by siRNA nanoparticles attenuated experimental ischemic stroke by promoting macrophage apoptosis and anti-inflammatory alternative activation. Identifying and targeting Maclpil human homolog(s) may help develop a novel therapy for stroke clinical management.